The goal of this project is to test the hypothesis that when the anti-hiv protease inhibitors are coadministered with drugs of abuse, clinically significant pharmacokinetic drug interactions will result. We will test this hypothesis in the macaques using a representative protease inhibitor, ritonavir which is a potent inhibitor of both cytochrome p450 3a4 and the multidrug resistance efflux pump, p glycoprotein. The drugs of abuse that we will test will be morphine and methadone. Specifically, our studies will test the major hypothesis that ritonavir will increase the concentrations of the narcotics in the cns by inhibiting their efflux via the p glycoprotein located at the blood brain barrier. In studies that we will conduct to test the above hypothesis we will also test the following subhypothesis. Ritanovir will increase the clearance of morphine to its glucuronide metabolites by induction of ugts. The disposition of ritonavir will be unaffected by narcotics. Studies will provide important data in a representative animal model to determine if studies should be conducted in the clinic to conform the presence of these interactions.